The present invention relates generally to invasive medical devices, and specifically to methods and devices for prevention and treatment of infections and thrombosis associated with the use of percutaneous, intravascular and intraluminal devices.
Invasive devices such as catheters, central venous catheters, drug delivery tubing, porta-caths, etc., which are passed through body orifices or through an opening made in the patient""s skin, are commonplace in medicine today. Such devices are referred to variously as xe2x80x9cpercutaneous,xe2x80x9d xe2x80x9cintravascularxe2x80x9d or xe2x80x9cintraluminalxe2x80x9d devices. Inherent in their use is the risk of systemic infection secondary to the growth of bacteria in their vicinity, due to the introduction of bacteria with their insertion or bacterial colonization in vivo, and the fluid stasis that can occur with blockage and thus serve as nidus for infection.
Despite innovations such as the local application of antibiotics, infection continues to occur. The organisms involved in these infections are more resistant to antibiotic treatment, presumably due to a change of their membrane permeability when adherent to a catheter surface, or possibly due to other causes. Life-threatening systemic infections can occur as a result. Therefore, medical staff need to regularly remove these invasive devices, disinfect the area, and re-insert a new device. This leads to further concomitant risk of infection, as well as being unpleasant, expensive, and vexing to both staff and patient. A device that would markedly decrease or totally eliminate the need for repetitive catheter replacement, could prove extremely beneficial and allow for a significant decrease in the associated morbidity as noted heretofore.
The accepted means of preventing or treating bacterial contamination is through the use of antibiotics. At the same time, it is widely recognized that the bacteria sequestered in a biofilm that forms on a medical implant are much more resistant to antibiotics than their planktonic counterparts. There have been reports that impregnation of catheters with antiseptics or antibiotics may be helpful in reducing bacterial colonization on the catheter and related bloodstream infection. A recent report to this effect was presented by Veenstra et al., in xe2x80x9cEfficacy of Antiseptic-Impregnated Central Venous Catheters in Preventing Catheter-Related Bloodstream Infection,xe2x80x9d published in the Journal of the American Medical Association, Vol. 281 (1999), pp. 261-267, which is incorporated herein by reference.
Studies have shown that the addition of low-frequency ultrasound simultaneous to the application of antibiotics enhances the effectiveness of the antibiotic in killing the bacteria. In vitro experiments to this effect were reported by Qian et al. in an article entitled, xe2x80x9cThe Effect of Ultrasonic Frequency upon Enhanced Killing of P. aeruginosa Biofilms,xe2x80x9d published in the Annals of Biomedical Engineering, Vol. 25 (1997), pp. 69-76, which is incorporated herein by reference. The authors found that when ultrasonic energy was applied to bacteria sequestered in a biofilm in conjunction with administration of an antibiotic (gentamicin), a significantly greater fraction of the bacteria were killed than by the antibiotic alone. Ultrasound by itself was not found to have any significant effect on the bacteria.
Similarly, Pitt et al. reported in an earlier article entitled xe2x80x9cUltrasonic Enhancement of Antibiotic Action on Gram-Negative Bacteria,xe2x80x9d in Antimicrobial Agents and Chemotherapy Vol. 38 (1994), pp. 2577-2582, which is incorporated herein by reference, that a synergistic effect was observed when ultrasound was applied in combination with gentamicin to in vitro bacterial biofilms. The authors suggest that these results may have application in the treatment of bacterial biofilm infections on implant devices. Ultrasound by itself was not found to be effective in inhibiting bacterial growth, except possibly at power levels high enough to cause cavitation (which would therefore damage surrounding tissues in the body, as well).
There have been a number of reports on the use of ultrasound in the treatment of wounds in vivo. For example, Yudin et al., in xe2x80x9cA Comparative Description of Effectiveness of Middling and Low Frequency Ultrasound in Treatment of Festering Wounds,xe2x80x9d published in Vestnik Khirurgii (1995), pp. 63-64, report that ultrasound can have a bactericidal effect in treating wound infection. Similar results were reported by Ukhov et al., in xe2x80x9cIndices of Immunity in Treating the Infected Wounds by Low-Frequency Ultrasound,xe2x80x9d published in Klin. Khir. (1990), pp. 10-12. Komrakov et al., in xe2x80x9cThe Use of Ultrasound and Antibiotics for the Treatment of the Wounds in Patients with a High Risk of Vascular Graft Infection,xe2x80x9d in Klin. Khir. (1990), pp. 10-11, report that low-frequency ultrasound in combination with gentamicin was effective in reducing the level of bacterial wound colonization following vascular graft. All of these articles are incorporated herein by reference.
Clinical ultrasound systems are mainly used for imaging, although there are also some therapeutic devices in use and others that have been suggested in the patent literature. For example, Talish, in PCT patent application PCT/US98/07531, whose disclosure is incorporated herein by reference, describes apparatus for ultrasonic bone treatment. The apparatus includes a therapeutic ultrasonic composite comprising a transducer and an integrated circuit unit positioned adjacent thereto. In operation, the apparatus is placed against the skin adjacent to a wound area, and driving signals are transmitted to the transducer for the creation of therapeutic ultrasound in the area of the bone. Another device of this type, for promotion of vascularization and epitheliazation of a wound inside the body, is described by Duarte et al., in U.S. Pat. No. 5,904,659, whose disclosure is also incorporated herein by reference.
A number of ultrasound devices for percutaneous and intrabody medical use have also been suggested. For example, PCT patent application PCT/IL97/00159, to Ben Haim et al., describes a self-aligning catheter, which uses ultrasound transducers inside the catheter to guide insertion of the probe through physiological tissues.
Tachibana et al., in PCT patent application PCT/US97/19993, whose disclosure is incorporated herein by reference, propose an intraluminal wall drug delivery device. A catheter, which is inserted into a blood vessel for this purpose, comprises at least one puncturing element that is laterally extendable to the catheter""s longitudinal axis at its distal end, an ultrasound emitter, and an introducer element that introduces medication into an injection site that is in or beyond the vessel wall. The introducer element delivers a drug for treating local stenosis in the vessel, while the ultrasound emitter generates ultrasound in order to improve the distribution of the drug in the area of the stenosis.
U.S. Pat. No. 5,725,494, to Brisken, whose disclosure is incorporated herein by reference, describes an ultrasonic catheter with a resonantly-vibrating assembly at its distal end for treating vascular clot and plaque. The distal end is positioned in the area of a clot or stenosis in a blood vessel, and the vibrating assembly administers ultrasonic energy to break up the clot or other stenotic lesions. The catheter may also be used in conjunction with a therapeutic agent.
It is an object of some aspects of the present invention to provide methods and devices for reducing the risks of infection and thrombosis associated with the use of invasive medical devices, and particularly for reducing risks of infection and thrombosis within a lumen into which the invasive device is inserted and in a vicinity of the lumen.
It is another object of some aspects of the present invention to provide methods and devices for treating infection, thrombosis or clotting associated with such invasive devices.
It is a further object of some aspects of the present invention to provide methods and devices for reducing the risks of infection associated with implanted or indwelling devices, such as vascular stents and Goretex vascular anastomoses, and with subcutaneous catheters, such as those used with insulin pumps.
A further object of some aspects of the present invention is to provide devices and methods for delivering ultrasonic energy to invasive devices that achieve good and more or less uniform coverage of the outer surfaces of the device.
Another object of some aspects of the present invention is to provide for a safe, disposable ultrasonic device that can be used intermittently on a patient and then discarded.
In preferred embodiments of the present invention, an ultrasonic transducer is coupled to a device that is inserted into the body of a patient, typically a percutaneous, intravascular and/or other intraluminal device, such as a catheter. While the device is inserted into a patient""s body, typically into a blood vessel, the transducer is actuated intermittently to apply ultrasonic energy to the device. Application of the energy, which is optionally accompanied by administration of therapeutic substances, such as antibiotics, anticoagulants and/or fibrinolytic agents, inhibits infection and thrombosis associated with the device. The effect of the ultrasonic energy can be both prophylactic, helping to prevent the occurrence of infection or clotting, and therapeutic, helping to treat the infection or clot if one does occur.
Preferred embodiments of the present invention thus reduce the morbidity associated with the use of invasive devices and enable such devices to be left in place in the body for longer periods than would normally be possible with invasive devices known in the art. Although the efficacy of ultrasound for treating infections and thromboses and in promoting wound healing is known in the art, as exemplified by the publications cited in the Background of the Invention, there has been no suggestion that ultrasound be used prophylactically in conjunction with an invasive device.
In some preferred embodiments of the present invention, the ultrasonic transducer is an integral part of the invasive device and is inserted into the body with the device. In other preferred embodiments, the transducer is attached to the invasive device externally, typically at a location external to the body after the device has been inserted. In this latter case, the transducer may be detached from the invasive device and reattached intermittently, in accordance with a schedule for administration of the prophylactic ultrasonic treatment. In either case, the transducer is preferably coupled and matched to the invasive device so as to transfer ultrasonic energy to all surfaces of the device that are in contact with body tissues and fluids.
In some preferred embodiments of the present invention, an ultrasonic generator is used to administer the ultrasonic energy, the generator comprising a battery and/or external power supply, and an integrated circuit module (ICM), which comprises a signal generator and an interface to the transducer, which is preferably a piezoelectric transducer. Preferably, the transducer is designed to provide directional amplification, or is equipped with a directional horn or other implement for facilitating delivery of the energy to the invasive device. Alternatively, the transducer may be designed as a point source or otherwise non-directional ultrasonic radiator.
The ICM preferably has electric impedance that matches, or is close to, that of the transducer. Further preferably, the ICM is programmable or otherwise adjustable so that different frequencies, intensity levels, and/or operating times can be set, depending on clinical needs and indications. The ICM is most preferably self-adjusting, to match the resonant frequency of the transducer, based on a microprocessor and/or other adjustable electrical circuit. The intensity is preferably maintained within two orders of magnitude of 0.1 W/cm2, that being the safe ultrasound radiation intensity for unlimited periods as determined by the American Institute of Ultrasound in Medicine. Additionally or alternatively, the ICM has an activating switch and on/off indicator.
The transducer preferably includes a matching layer, that optimizes acoustic wave energy transfer from the transducer to the adjacent fluids, invasive devices or body organs, respectively.
In one preferred embodiment of the present invention, the ultrasonic generator comprises a small, easily movable structure attached to the outer part of the invasive device via a spring. The transducer is mounted either in parallel to the axis of the catheter or at an angle, so that vibrational energy can be transferred to the catheter in a direction perpendicular to its axis, along its axis, or via a combination of the two.
In another preferred embodiment of the device, the transducer is tubular in shape and is embedded in the catheter tube itself. Another, similar embodiment uses a transducer of a striped shape with one or more elements, rather than tubular as the aforementioned. These shapes allow the ultrasonic energy to be administered close to the surfaces where it is most effective, and allow for the use of a smaller battery and/or longer operating periods. Similarly, the use of directional guides to direct the wave energy into the inserted parts of the invasive device reduces the needed energy supply.
In other preferred embodiments, the transducer and possibly the ICM are built so as to be located between a proximal end of the catheter and a tube coupled to the proximal end that conveys a fluid, such as a therapeutic agent, to the catheter. Preferably, the transducer is fully immersed in the fluid, and the ultrasonic energy is thus transferred by vibrations in the fluid to other parts of the catheter within the patient""s body.
In other preferred embodiments of the invention, the ultrasonic energy is applied to implanted devices, such as vascular stents or Goretex vascular anastomoses. Preferably, the ultrasonic transducer is integrated with the implanted device. The ICM and the activation batteries are optionally also integrated with the implanted device, or alternatively, they are external to the body. Further alternatively, the ultrasonic energy is applied from outside the body through an insertion device. As a still further alternative, the transducer is attached to the skin or to a balloon-type fluid container that is firmly attached to the skin. The ultrasound energy is radiated from the transducer, through the fluid in the balloon, to an intravascular tube in a vein or artery or to the implanted device itself that is below the skin.
There is therefore provided, in accordance with a preferred embodiment of the present invention, a method for reducing morbidity associated with a medical device inserted into the body of a patient, including applying ultrasonic energy to the device with sufficient intensity to inhibit accretion of biological matter associated with the device while the device is in the body. Preferably, applying the ultrasonic energy includes applying energy to the device in the absence of clinically-observable accretion of biological matter on the device so as to prevent such accretion.
In some preferred embodiments, applying the ultrasonic energy includes integrating an ultrasonic transducer in the device and actuating the transducer.
In other preferred embodiments, applying the ultrasonic energy includes coupling a source of ultrasonic energy outside the body to the invasive device in the body. Preferably, coupling the source of ultrasonic energy includes fixing a transducer to a portion of the invasive device that is outside the body. Alternatively, coupling the source of ultrasonic energy includes transferring energy to a fluid that passes through the invasive device, wherein transferring the energy to the fluid includes immersing at least a portion of the transducer in the fluid. Further alternatively, coupling the source of ultrasonic energy includes coupling a transducer to the skin of the body adjacent to a location of the invasive device in the body.
Preferably, applying the ultrasonic energy includes applying energy to the device so as to inhibit bacterial growth on the device. Additionally or alternatively, applying the ultrasonic energy includes applying energy to inhibit formation of a clot on the device.
In a preferred embodiment, the method includes administering a therapeutic agent in a vicinity of the device inside the body in conjunction with applying the ultrasonic energy. Preferably, the therapeutic agent includes an antibacterial agent or, alternatively or additionally, an anti-clotting agent. Most preferably, administering the therapeutic agent includes coating at least a portion of the device with the therapeutic agent.
There is also provided, in accordance with a preferred embodiment of the present invention, apparatus for reducing morbidity associated with a device inserted into the body of a patient, including an ultrasonic energy generator, which is coupled to apply ultrasonic energy to the device with sufficient intensity to inhibit accretion of biological matter associated with the device while the device is in the body.
Preferably, the ultrasonic energy generator includes an ultrasonic transducer and an integrated circuit module, which drives the transducer so as to control one or more parameters of the energy applied to the device. Most preferably, the integrated circuit module generates an oscillating electrical current to drive the transducer, and wherein the module adjusts a frequency of the oscillating current so as to match a resonant frequency of the transducer. Optionally, the integrated circuit module is coupled to the transducer by a connector, so that a portion of the apparatus containing the transducer may be disposed of after use or be sterilizable, while another portion including the integrated circuit module is reused.
There is further provided, in accordance with a preferred embodiment of the present invention, an ultrasonic energy generator for use with an invasive device, including:
a generator body, adapted to be mechanically coupled to a proximal portion of the invasive device that is outside the body; and
a transducer, held by the generator body so as to apply ultrasonic energy to the invasive device while a distal portion of the device is in the body.
Preferably, the generator body includes a fastener, which is adapted to fix the transducer to the invasive device. Alternatively or additionally, the generator body is shaped so as to be insertable into a lumen of the invasive device.
Further alternatively or additionally, the generator body includes a fluid container, containing a fluid that passes through the invasive device, and the transducer is coupled to transfer ultrasonic energy to the device through the fluid. Preferably, at least a portion of the transducer is immersed in the fluid. Further preferably, the container is shaped so as to concentrate the ultrasonic energy from the transducer into the device.
There is moreover provided, in accordance with a preferred embodiment of the present invention, a medical device, including:
an intrabody member, for insertion into the body of a patient; and
an ultrasonic energy generator, which is coupled to apply ultrasonic energy to the intrabody member with sufficient intensity to inhibit accretion of biological matter associated with the device while the device is in the body.
Preferably, the ultrasonic energy is applied in conjunction with administration of a therapeutic agent in a vicinity of the intrabody member inside the body, wherein the therapeutic agent is most preferably adherent to a surface of the intrabody member. Alternatively, the therapeutic agent is injected into the body through the intrabody member or via other means, and is used according to its pharmaco-kinetics.
In a preferred embodiment, the intrabody member includes a catheter. In another preferred embodiment, the intrabody member includes an implanted element, such as a vascular implant. In still another preferred embodiment, the intrabody member includes a short-term transcutaneous insert, wherein most preferably, the device includes a pump, which is coupled to inject a fluid into the body through the insert, and an energy source for driving the ultrasonic generator, which is integrated with the pump.
There is additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for reducing morbidity associated with a device inserted into the body of a patient, including an ultrasonic transducer, which is coupled to the skin of the body adjacent to a location of the device in the body and is adapted to apply ultrasonic energy through the skin to the device with sufficient intensity to inhibit accretion of biological matter associated with the device while the device is in the body.
There is also provided, in accordance with a preferred embodiment of the present invention, a method for reducing morbidity associated with a medical device inserted into the body of a patient, including:
coupling a transducer to an outer surface of the body adjacent to a location of the device in the body; and
applying ultrasonic energy to the device through the outer surface of the body with sufficient intensity to inhibit accretion of biological matter associated with the device while the device is in the body.
There is still further provided, in accordance with a preferred embodiment of the present invention, a medical device, including:
a tubular member for insertion into the body of a patient, the member comprising a wall that defines a lumen therethrough; and
an ultrasonic energy generator, which is coupled to apply ultrasonic energy to the wall of the tubular member with sufficient intensity to inhibit accretion of biological matter associated with the device while the device is in the body.
Preferably, the ultrasonic energy generator comprises an ultrasonic transducer, which is integrally contained within the wall of the tubular member. Additionally or alternatively, the ultrasonic energy generator is generally tubular, and has a diameter similar to a diameter of the tubular member.
The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings in which: